Editors' ChoiceCancer

Bidirectional Dance of Glutamine

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Science Translational Medicine  25 Jan 2012:
Vol. 4, Issue 118, pp. 118ec12
DOI: 10.1126/scitranslmed.3003732

Although most dancers have a dominant leg that drives the performer’s tendency to rotate in one direction across a stage, choreography sometimes demands otherwise. Like ballet masters, the body can specify a restaging, in this case of metabolism at the cellular level. The versatile amino acid glutamine can perform its metabolic dance in two different directions depending on the cell type and microenvironment, including oxygen and nutrient availability. Now, Metallo et al. investigate how cancer cells and their surroundings choreograph the metabolic reactions of this most abundant amino acid in the human body.

Rapidly dividing cancer cells reprogram their metabolism to compensate for increased energy demands and macromolecular synthesis needs. In cells, lipid biosynthesis using glutamine as a substrate can occur by two different pathways. The glutaminase enzyme converts glutamine to glutamate and produces ammonia in the process. Glutamate is then converted to α-ketoglutarate (αKG), an intermediate in the energy-generating tricarboxylic acid (Krebs) cycle. Cells either can oxidize αKG via the Krebs cycle, generate malate through a series of reactions, and then produce pyruvate by a process called glutaminolysis, or can convert αKG, by reductive carboxylation, to citrate. In the first pathway, pyruvate is converted, in mitochondria, to acetyl coenzyme A (AcCoA), which is a precursor of lipid biosynthesis. On the other hand, citrate derived from the second pathway is transported to the cytoplasm and then broken down to AcCoA. To determine the dominant pathway for lipogenesis in cancer cells, Metallo et al. grew a variety of cell lines in culture in the presence of various 13C-labeled glutamine tracers.

The researchers found that in cancer cell lines derived from lung, mammary, colon cancers, squamous cell carcinoma, melanoma, glioblastoma, or leukemia, most of the AcCoA was derived from glutamine via reductive carboxylation, which thus may be the primary route through which glutamine is converted to lipids in cultured cancer cells. The glutaminolysis pathway also occurred in these cells, as evidenced by the detection of the glutamine-derived 13C label in lactate, which reached the highest amount in glioblastoma-derived cells as compared with other cultured cancer cells. The reductive carboxylation pathway was dependent mainly on the catalytic activity of isocitrate dehydrogenase-1 (IDH1), which can convert reduced nicotinamide adenine dinucleotide phosphate, αKG, and carbon dioxide to isocitrate and NADP+ in the cytosol. The IDH gene is known to be mutated in several types of cancers.

Insufficiency of blood supply for rapidly growing tumors generates areas within tumors that have low oxygen concentrations (hypoxia). The authors demonstrated that cells preferentially used glucose carbon for fatty acid synthesis under normoxic conditions, compared with dominantly glutamine-derived fatty acid production under hypoxic conditions. A significant decrease in the proliferation of cancer cells was observed in the absence of glutamine under hypoxic conditions, which highlights the glutamine dependency of such cells. Last, renal cell carcinoma cell lines deficient in the von Hippel–Lindau tumor suppressor protein preferentially used reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels probably by activating hypoxia inducible factor signaling.

These results suggest that, like a talented dancer, glutamine metabolism in cancer cells can change directions in response to external conditions. But the current findings are based on data in cultured cells, and further in vivo study is needed. Nonetheless, considering the recently discovered mutations in metabolic enzymes such as IDH1 and the glutamine addiction phenomenon observed in a subset of cancers, it is possible that the authors have pinpointed several new enzymes within glutamine metabolic pathways for targeting hematological malignancies and solid tumors.

C. M. Metallo et al., Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011). [PubMed]

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